Twenty-Year Clinical Progression of Dysferlinopathy in Patients from Dagestan

Umakhanova, Zoya R.; Бардаков, С. Н.; Мавликеев, М. О.; Chernova, Olga N.; Магомедова, Р. М.; Akhmedova, Patimat G.; Yakovlev, Ivan A.; Dalgatov, Gimat D.; Федотов, Валерій Павлович; Исаев, А. А.; Деев, Р. В.

doi:10.3389/fneur.2017.00077

Cited by 11 publications

(30 citation statements)

References 13 publications

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“…Postural abnormalities have been reported previously in patients with MD of the Duchenne type and in dysferlinopathies (Hsu & Furumasu, 1993;Mahjneh et al 2001;Pradhan et al 2006). In general, MD patients suffer from sudden spontaneous falls, balance problems, as well as gait and posture abnormalities (Barrett et al 1988) or kinematic and mechanical deficits as well as a peripheral areflexia (Fukuda et al 1999;Umakhanova et al 2017). Some of these symptoms can certainly be attributed to the muscle weakness.…”

Section: Discussionmentioning

confidence: 83%

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Impaired muscle spindle function in murine models of muscular dystrophy

Gerwin

Rossmanith

Haupt

et al. 2020

The Journal of Physiology

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Key points Muscular dystrophy patients suffer from progressive degeneration of skeletal muscle fibres, sudden spontaneous falls, balance problems, as well as gait and posture abnormalities. Dystrophin‐ and dysferlin‐deficient mice, models for different types of muscular dystrophy with different aetiology and molecular basis, were characterized to investigate if muscle spindle structure and function are impaired. The number and morphology of muscle spindles were unaltered in both dystrophic mouse lines but muscle spindle resting discharge and their responses to stretch were altered. In dystrophin‐deficient muscle spindles, the expression of the paralogue utrophin was substantially upregulated, potentially compensating for the dystrophin deficiency. The results suggest that muscle spindles might contribute to the motor problems observed in patients with muscular dystrophy. Abstract Muscular dystrophies comprise a heterogeneous group of hereditary diseases characterized by progressive degeneration of extrafusal muscle fibres as well as unstable gait and frequent falls. To investigate if muscle spindle function is impaired, we analysed their number, morphology and function in wildtype mice and in murine model systems for two distinct types of muscular dystrophy with very different disease aetiology, i.e. dystrophin‐ and dysferlin‐deficient mice. The total number and the overall structure of muscle spindles in soleus muscles of both dystrophic mouse mutants appeared unchanged. Immunohistochemical analyses of wildtype muscle spindles revealed a concentration of dystrophin and β‐dystroglycan in intrafusal fibres outside the region of contact with the sensory neuron. While utrophin was absent from the central part of intrafusal fibres of wildtype mice, it was substantially upregulated in dystrophin‐deficient mice. Single‐unit extracellular recordings of sensory afferents from muscle spindles of the extensor digitorum longus muscle revealed that muscle spindles from both dystrophic mouse strains have an increased resting discharge and a higher action potential firing rate during sinusoidal vibrations, particularly at low frequencies. The response to ramp‐and‐hold stretches appeared unaltered compared to the respective wildtype mice. We observed no exacerbated functional changes in dystrophin and dysferlin double mutant mice compared to the single mutant animals. These results show alterations in muscle spindle afferent responses in both dystrophic mouse lines, which might cause an increased muscle tone, and might contribute to the unstable gait and frequent falls observed in patients with muscular dystrophy.

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Section: Discussionmentioning

confidence: 83%

“…1999; Umakhanova et al . 2017). Some of these symptoms can certainly be attributed to the muscle weakness.…”

Section: Discussionmentioning

confidence: 99%

Impaired muscle spindle function in murine models of muscular dystrophy

Gerwin

Rossmanith

Haupt

et al. 2020

The Journal of Physiology

View full text Add to dashboard Cite

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“…Despite the pronounced clinical variability of the disease in families, the authors of one of the studies note that at the onset of the disease the symptoms within the same family were similar, that is, if someone in the family was diagnosed with MM, then other family members with the same mutations also had MM 33 . Moreover, there is a clear tendency to have the same phenotype within the same generation of brothers and sisters 41 . However, data from other studies suggest the opposite 5,51,52 …”

Section: Genotype–phenotype Correlationsmentioning

confidence: 99%

Dysferlinopathies: Clinical and genetic variability

2022

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Dysferlinopathies are a clinically heterogeneous group of diseases caused by mutations in the DYSF gene encoding the dysferlin protein. Dysferlin is mostly expressed in muscle tissues and is localized in the sarcolemma, where it performs its main function of resealing and maintaining of the integrity of the cell membrane. At least four forms of dysferlinopathies have been described: Miyoshi myopathy, limb‐girdle muscular dystrophy type 2B, distal myopathy with anterior tibial onset, and isolated hyperCKemia. Here we review the clinical features of different forms of dysferlinopathies and attempt to identify genotype–phenotype correlations. Because of the great clinical variability and rarety of the disease and mutations little is known, how different phenotypes develop as a result of different mutations. However, missense mutations seem to induce more severe disease than LoF, which is typical for many muscle dystrophies. The role of several specific mutations and possible gene modifiers is also discussed in the paper.

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“…One approach to identify the underlying mechanisms is to study patient cohorts from different ethnic origins. Different DYSF mutations have been identified in various ethnicities ( 8 – 10 ), although few studies focused on Chinese patients ( 11 , 12 ).…”

Section: Introductionmentioning

confidence: 99%

Abnormal Expression of Dysferlin in Blood Monocytes Supports Primary Dysferlinopathy in Patients Confirmed by Genetic Analyses

Zhang

Cheng

et al. 2021

Front. Neurol.

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Objective: Dysferlin deficiency causes dysferlinopathy. This study aimed to expand the mutational spectrum of dysferlinopathies, to further study one case with diagnostic ambiguity, and to identify the diagnostic value of dysferlin expression in total peripheral blood mononuclear cells (PBMC).Methods: The clinical and molecular profiles of dysferlinopathies in eight Chinese patients were evaluated. We also conducted magnetic resonance imaging (6/8) and determined dysferlin protein expression in muscle (7/8) and PBMC (3/8).Results: Nine of the 13 DYSF mutations identified were novel. One patient was homozygous for the Gln111Ter mutation by genomic DNA sequencing but was found to be heterozygous by sequencing of cDNA from total PBMC. A daughter of this patient did not carry any Gln111Ter mutation. Abnormal muscle MRI with predominant involvement of the medial gastrocnemius and soleus muscle was observed in 5/6 patients. Dysferlin levels were significantly reduced (immunohistochemistry/immunoblot) or absent (immunohistochemistry) in muscle and total PBMC (26–39%) for most patients. Sarcoplasmic accumulation of dysferlin was detected in one patient.Conclusion: Genomic DNA sequencing detects frequent homozygous mutations, while fewer heterozygous mutations in cDNA are detected after posttranscription. Total PBMC may serve as an alternative to confirm diagnosis and to guide further testing in dysferlinopathies. Our results contribute to the mutational spectrum of dysferlinopathies.

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Twenty-Year Clinical Progression of Dysferlinopathy in Patients from Dagestan

Cited by 11 publications

References 13 publications

Impaired muscle spindle function in murine models of muscular dystrophy

Impaired muscle spindle function in murine models of muscular dystrophy

Dysferlinopathies: Clinical and genetic variability

Abnormal Expression of Dysferlin in Blood Monocytes Supports Primary Dysferlinopathy in Patients Confirmed by Genetic Analyses

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